Nadia Chaudhri’s presentation challenged the widely held belief that smoking is driven solely by the direct, pharmacological actions of nicotine in the brain. Her team, using a standard model of drug self-administration in rats, collected data showing that nicotine reinforcement is strongly influenced by the interaction between nicotine and nonpharmacological environmental stimuli. Furthermore, they determined that this interaction does not require the response-contingent delivery of nicotine, suggesting that primary reinforcement is not the exclusive mechanism underlying nicotine addiction.

The team’s findings indicate that the rapid, robust levels of operant responding observed during the acquisition and maintenance of nicotine self-administration result from a synergistic interaction between nicotine and non-drug stimuli. Furthermore, this synergism appears to reflect two separable actions that Chaudhri termed the “dual-reinforcing effects of nicotine.” The dual-reinforcing hypothesis states that in addition to acting as a primary reinforcer, nicotine can enhance the reinforcing value of other stimuli in a manner that is not dependent on a close temporal association between nicotine and other stimuli, or the behavior controlling their delivery.

Nicotinic acetylcholine receptors (nAChR) are involved in various pharmacological effects of nicotine and are altered in various disease states, such as schizophrenia, Parkinson’s, and Alzheimer’s diseases. The goal of Dr. Yu-Shin Ding’s research was to develop suitable PET radioligands to study nAChR in humans. Using F-18-labeled nicotinic agonists, 2–[18F]fluoro-A-85380 (2–[18F]FA) and 6-[18F]fluoro-A-85380 (6-[18F]FA), his research team carried out comparative PET studies in both baboons and humans. They concluded that 6-[18F]FA displays high brain uptake in baboons and that the distribution of radioactivity was consistent with that of nAChR in humans. Their results demonstrated that: (1) 6-[18F]FA is a suitable radioligand for quantitative PET studies of nAChR in the human brain, and that a total 4-hour study with 2 hours of actual scanning time is adequate for kinetic analysis; (2) the binding of 6-[18F]FA is specific to nAChR and can be displaced by the nicotine in cigarettes; and (3) white matter binding of 6-[18F]FA is specific for nAChR. These studies also showed that 6-[18F]FA is a potentially useful in vivo tool to better understand the role of nAChR in various diseases and their relationship with the abnormality in white matter.

Various neural systems have been implicated in the processing of nicotine’s bivalent motivational properties. However, considerable evidence points to a central role for the ventral tegmental area (VTA) and the functionally associated mesolimbic dopamine (DA) system and brainstem pedunculopontine nucleus as critical players in the central processing of nicotine’s rewarding and aversive psychological properties. Dr. Steven Laviolette’s research suggests that in the acute phase of nicotine exposure, the rewarding effects of nicotine are dependent on the pedunculopontine nucleus, while DA transmission signals the aversive effects of nicotine. However, following chronic exposure to nicotine, the motivational effects of continued nicotine use may depend on transmission through the mesolimbic DA system.

This presentation discussed the emerging characterization of separate dopaminergic and GABAergic neural systems within the VTA that can mediate either the acute rewarding or aversive psychological effects of nicotine versus the motivational effects of nicotine in the dependent and addicted state, providing new insights into (1) how functional interactions between these systems may determine vulnerability to nicotine addiction, and (2) how continued exposure to nicotine may induce plastic molecular alterations within the VTA, triggering an “addiction switch” to a state of nicotine dependence, craving, and compulsive nicotine use.

Two factors that lead to drug dependence, including habitual tobacco smoking, are the rewarding effects of drugs of abuse and the motivation to alleviate the negative affective aspects of drug withdrawal. Dr. Athina Markou suggested in her presentation that cholinergic-glutamatergic-GABAergic interactions in the ventral tegmental area (VTA) and other brain sites may be critically involved in mediating the rewarding effects of nicotine, and may exhibit adaptations with the development of nicotine dependence that contribute to nicotine withdrawal. GABA is the main inhibitory neurotransmitter and glutamate is the main excitatory neurotransmitter in the brain. Dr. Markou discussed the methods and results of her research examining nicotine self-administration in rats, as well as cue-induced reinstatement of nicotine-seeking behavior. Dr. Markou also gave an overview of her research team’s investigations involving the role of mGlu2/3 receptors, possibly mediating the negative affective aspects of nicotine withdrawal.

The restricted localization of the dopamine (DA) D3 receptor in key elements of the mesolimbic DA system in both the rat and human brain has led to the hypothesis that it may play an important role in drug addiction. This presentation focuses on recent advances in the DA D3 system that may lead to the development of new pharmacotherapies. Virtually all drugs of abuse activate the mesolimbic DA system. The enhanced extra-synaptic release of DA facilitates incentive-learning or the attribution of positive-incentive salience to cues. Thus, any responses to drugs that occur during the period of raised extra-synaptic DA have the potential to produce positive-incentive salience and to contribute to dependence. Dr. Christian Heidbreder introduced evidence suggesting that selective antagonism of DA D3 receptors may represent a unique pharmacotherapeutic strategy for treating drug-seeking and drug-taking behaviors. Specifically, he showed that SB-277011-A has significant efficacy in a wide range of behavioral paradigms assessing the abuse properties of nicotine, alcohol, cocaine, and heroin. His team of researchers used different experimental animal paradigms to assess the effects of SB-277011-A, and each had unique relevance for different aspects of human drug addiction. Altogether, their findings suggest that selective DA D3 receptor antagonism may hold the highest promise for attenuating cue-, drug-, or stress-evoked relapse to addictive drug use.